Introduction

The role of digitalis for the treatment of dropsy was first described by William Withering in 1785 [1]. Since that era, our understanding of heart failure has evolved through clinical and scientific discovery or as Katz describes the nine paradigms: clinical syndrome, circulatory disorder, altered architecture of the heart, abnormal hemodynamics, disordered fluid balance, biochemical abnormalities, maladaptive hypertrophy, genomics, and epigenetics [2]. Management over the last 50 years has been galvanized by the advent of vasodilators, inotropes, beta blockers, and neurohormonal blockade followed by the utilization of mechanical devices such as an implantable cardiac defibrillator, cardiac resynchronization therapy, pulmonary artery pressure sensor monitoring, and mechanical circulatory support (Fig. 1).

Fig. 1
figure 1

Current armamentarium for chronic systolic heart failure. Adapted from BJPCN with their permission [3]. Choosing an intervention(s) should be done with purpose and based on current guideline recommendations [4,5,6]. *This therapy is not currently endorsed by the guidelines. A recent study demonstrated a 30% reduction in heart failure re-hospitalizations and improved quality of life when used to tailor therapy and multiple trials are ongoing (see clinicaltrials.gov) [7]. ** Bisoprolol, carvedilol, and metoprolol succinate are the only beta-blockers approved for the treatment of HFrEF to reduce morbidity and mortality. ACE angiotensin converting enzyme, ACEi angiotensin converting enzyme inhibitor, ANP atrial natriuretic peptide, ARB angiotensin receptor blocker, BNP brain natriuretic peptide, Na sodium, RAAS renin-angiotensin-aldosterone system

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Despite these management advances, this complex condition currently affects over 6 million individuals [8]. Prevalence continues to rise alongside an aging, multi-comorbid population and mortality remains high with an estimated 50% at 5 years [8]. It is the primary diagnosis for over 1 million hospitalizations with an astounding 25%, 1 month re-admission rate [4]. Each re-admission has demonstrated a cumulative significant increase in mortality [9]. Rising prevalence and utilization of healthcare resources has placed a burden on healthcare spending with recent estimates at 30 billion dollars [4, 8].

In light of this dilemma, new approaches are needed. This review will focus on three recent novel therapeutic interventions that have demonstrated an impact on heart failure hospitalizations, morbidity, and/or mortality and one agent that may be able to solve one barrier to achieving optimal guideline-based treatment (Table 1) [4,5,6, 8].

Table 1 Novel therapies in patients with chronic systolic heart failure
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Novel therapeutics

Angiotensin receptor—neprilysin inhibition

Blockade of the renin-angiotensin-aldosterone system (RAAS) is the cornerstone of chronic, systolic heart failure therapy in the modern era with proven benefits in both cardiovascular morbidity and mortality [4, 17,18,19,20,21]. Atrial and brain natriuretic peptides, alongside adrenomedullin, have demonstrated an additive benefit in individuals living with heart failure by promoting vasodilation, natriuresis, and diuresis. Neprilysin is an endopeptidase that breaks down these vasodilator peptides and others including bradykinin, whose inhibition promotes reduction of pulmonary and systemic vascular resistance, decrease in serum aldosterone and fibrosis, yielding an augmentation of cardiac output and amelioration of congestion [22].

Sacubitril is a neprilysin inhibitor. Used alone, it did not show convincing beneficial effects because in addition to degrading vasodilator peptides like adrenomedullin, neprilysin also degrades potent vasoconstrictors such as angiotensin II and endothelin I. The combined impact therefore canceled each other out [23]. It was hypothesized that combination of neprilysin inhibition with suppression of angiotensin II via an angiotensin-converting enzyme inhibitor (ACEi) would solve this problem. The combination of sacubitril with an ACEi was achieved with omapatrilat. Unfortunately, this combination resulted in an unacceptably high rate of angioedema due to increased levels of circulating bradykinin [24, 25]. To mitigate this adverse effect, neprilysin inhibition was combined with an angiotensin receptor blocker (ARB). With this notion, LCZ696 was born, a combination of valsartan and sacubitril now known as an angiotensin II receptor blocker-neprilysin inhibitor (ARNI) [23].

PARADIGM-HF was a double-blind, randomized control trial evaluating cardiovascular outcomes in patients with chronic, systolic heart failure receiving either standard of care therapy with enalapril versus LCZ696 [10]. The primary outcome of this trial was a composite of cardiovascular mortality and heart failure hospitalization. The study was stopped prematurely due to an overwhelming mortality benefit. Compared to enalapril, LCZ696 achieved a 21.8% relative risk reduction (RRR) in cardiovascular death or hospitalization for heart failure, yielding a number needed to treat (NNT) of 21. There was also a significant reduction in cardiovascular death and heart failure hospitalization. A subsequent analysis of data from this trial showed that patients receiving LCZ696 had significantly lower rates of emergency department visits, less intensive care admissions, and were less likely to require intravenous inotropes [26]. With regard to adverse effects, the LCZ696 cohort exhibited a higher frequency of symptomatic hypotension, but a lower frequency of elevated serum creatinine, hyperkalemia, and cough. There were no reported episodes of severe angioedema in either group [10].

While this study was overwhelmingly positive, there were some criticisms. For instance, the chosen control drug was an ACEi, whereas the study drug contained an ARB. This was justified by stronger clinical evidence supporting ACEi compared to ARB for heart failure mortality and morbidity benefit. The dose of enalapril was also lower than the maximum dose-recommended in guidelines (40 versus 18.9 mg). However, this was the highest mean dose achieved in prior clinical studies [27, 28]. The initial dropout rate was approximately 20% during the initial run-in phase of the trial, but the rates were similar between the two arms. Additional concerns regarding the study drug’s applicability have also been raised secondary to the trial’s baseline demographics which included a predominantly Caucasian, male, European cohort with predominately NYHA functional class II symptomology. There have also been concerns raised regarding cost, although cost effectiveness analysis has shown positive results, and drug assistance programs are available [29].

Regardless, this landmark trial was subsequently incorporated into the 2016 American Heart Association guidelines for the management of patients with chronic systolic heart failure. The use of an ARNI is now a class I indication for this NYHA functional class II-III, level of evidence B-R, and should be used in combination with beta-blockade (BB) and mineralocorticoid receptor antagonist (MRA) therapies [6]. Providers should know that the addition of an ARNI in individuals previously receiving an ACEi requires a minimum of 36-h wash-out period to avoid the additional risk of angioedema [6].

If channel antagonist

Elevated resting heart rate serves as a marker for increased morbidity and mortality in individuals living with heart failure [30,31,32]. Reduction in heart rate may be achieved via BB, which continues to play a crucial role in heart failure with reduced ejection fraction (HFrEF) management [4, 33]. However, achieving a target dose may be limited by adverse effects, such as hypotension. Ivabradine is another novel agent that selectively inhibits the If channel within the sino-atrial node [34]. The net effect leads to a decrease in heart rate and prolonged diastolic filling time while preserving contractility and atrioventricular (AV) nodal conduction [35].

The SHIFT trial was a randomized, double-blind, placebo-controlled trial that investigated the impact of ivabradine therapy in 6505 patients with chronic, symptomatic HFrEF who had at least one hospitalization for heart failure in the last 12 months and a resting heart rate greater than 70 beats per minute (bpm). Heart rate reduction with ivabradine demonstrated a significant reduction in cardiovascular death or heart failure hospitalization, with a hazard ratio of 0.82 and an absolute risk reduction of (ARR) 5%. This primary composite outcome was heavily influenced by heart failure hospital admissions. In isolation, mortality reduction was not found to be significant in cardiovascular nor all-cause death. However, there was a significant decrease in mortality due to death from heart failure [11]. Subsequent subgroup analysis showed that the benefits of ivabradine plus BB were independent of baseline BB dose and were due to the magnitude of heart rate reduction [36]. Although this remains an area of criticism, as only 25% of patients in the ivabradine arm were receiving the guideline-recommended target BB dose [4, 11]. Thus, it is important to achieve the highest tolerated dose of BB prior to consideration of If antagonist therapy, both due to the pleiotropic effects of BB and to avoid polypharmacy.

Overall, the drug was found to be well tolerated and safe. However, some common adverse reactions included severe symptomatic bradycardia, atrial fibrillation, and ocular phosphenes or transient enhanced brightness [11]. Based on SHIFT and other studies, ivabradine now has a class IIA recommendation, level of evidence B-R, for treatment in individuals with chronic symptomatic HFrEF. This recommendation is contingent upon your patient being in sinus rhythm, receiving maximal tolerated BB dose, and having a resting heart rate greater than 70 bpm [6, 11, 36,37,38,39,40].

Sodium glucose cotransporter-2 inhibitors

Diabetes mellitus (DM) is a common and important comorbid condition in patients with heart failure. Diabetes doubles the risk of heart failure in males and confers a fivefold increased risk in females. The presence of heart failure serves as an independent risk factor for DM [41, 42]. The prevalence of DM continues to increase up to 30–35% in recent heart failure drug trials compared to earlier studies in which only 25% of heart failure patients had diabetes [10, 19, 40]. The relationship between diabetes and cardiovascular disease, specifically heart failure, continues to evolve. It is well known that diabetes leads to impaired endothelial function and subsequently a decrease in myocardial flow reserve. The phenomenon of “diabetic cardiomyopathy” involves the development of myocyte hypertrophy, interstitial fibrosis, microangiopathy, and altered myocardial energetics resulting in deterioration in cardiac function. This is further confounded by a highly activated sympathetic system and RAAS leading to impaired glucose metabolism and increased production of free fatty acids which in turn increases myocardial oxygen demand [42]. Despite the inextricable links between diabetes and heart failure, improvement in glycemic control has yet to demonstrate a risk reduction in macrovascular disease: coronary artery disease, peripheral artery disease, and stroke nor heart failure [43]. Indeed, some classes of diabetic drugs’ potential adverse effects may even increase the risk of heart failure [44]. Therefore, it is paramount to ensure the safety of novel diabetic medications in patients with cardiovascular disease.

Sodium glucose cotransporter-2 (SGLT2) is responsible for 90% of renal glucose reabsorption within the nephron’s proximal tubule [45]. Inhibition of this cotransporter increases urine glucose excretion, decreasing serum glucose levels independently of insulin production or insulin sensitivity [46]. Empagliflozin is a selective inhibitor of SGLT2 and has been approved for the treatment of type II DM as a mono or adjunctive therapy [47]. Early evidence suggests that empagliflozin is associated with improvements in peripheral vascular resistance, blood pressure, weight control, and decrease in glycated hemoglobin (HbA1c) [47, 48]. Its effects on cardiovascular morbidity and mortality were recently investigated.

EMPA-REG OUTCOME was a randomized, double-blind, placebo-controlled trial which investigated the impact of empagliflozin on cardiovascular morbidity and mortality in individuals with type II diabetes mellitus and established cardiovascular disease. The trial’s primary outcome was a composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke and demonstrated a significant reduction in the empagliflozin arm with a hazard ratio of 0.86 (0.74–0.99), 95% confidence interval with a p = 0.04 for superiority and p < 0.001 for non-inferiority. Secondary endpoints demonstrated a significantly lower risk of death from cardiovascular causes, death from any cause, and heart failure hospitalization [48]. The empagliflozin cohort demonstrated a 5.1% ARR in heart failure hospitalizations and 10.5% ARR in the composite endpoint of heart failure hospitalizations or cardiovascular death (see supplemental appendix, Table S4) and a 38% RRR in cardiovascular mortality [48]. It is important to note that heart failure patients comprised only 10% of the total study population; this was based on investigator reporting and was not defined by ejection fraction or functional class [12, 48]. Subgroup analyses between the presence and absence of heart failure was performed and continued to demonstrate an event risk reduction within the empagliflozin arm compared to placebo [12].

Overall, SGLT2 inhibitors are well tolerated but adverse effects can occur. Most common side effects include hypoglycemia, urinary tract infections, and genital infections. Another rare but serious side effect of SGLT2 inhibition is euglycemic diabetic ketoacidosis [47,48,49]. Subsequently, in December 2016, empagliflozin was approved by the Food and Drug Administration (FDA) for reduction in cardiovascular death in patients with type II diabetes mellitus and established cardiovascular disease [50]. Consideration of this therapy has been endorsed by the 2016 European Society of Cardiology guidelines to prevent or delay the onset of heart failure [5]. It has yet to be incorporated into the American guidelines.

Other SGLT2 inhibitors including dapagliflozin and canagliflozin are currently undergoing investigation in patients with heart failure [51, 52]. The mechanism(s) behind the beneficial, pleiotropic effects of SGLT2 inhibition as demonstrated by EMPA-REG OUTCOME warrants further investigation to further elucidate and solidify the benefits in patients living with heart failure.

Oral potassium binders

Hyperkalemia is a well-known complication of RAAS blockade which is further exacerbated in heart failure patients secondary to their physiology and comorbidities including chronic kidney injury and diabetes mellitus. Aside from dietary potassium restriction, traditional oral agents that exist for treatment of chronic hyperkalemia include diuretics, fludrocortisone, and cation exchange resins, such as sodium polystyrene sulfate. The latter two are often not well tolerated secondary to adverse reactions including: hypertension, fluid retention, and gastrointestinal side effects further complicated by slow onset of action [53]. Pivotal MRA heart failure trials demonstrated relatively low rates of hyperkalemia (<6%) [54,55,56]. And yet, the more recent ARNI study demonstrated this was a more common complication, approximately 15% of patients receiving either sacubitril-valsartan or enalapril developed hyperkalemia as defined by a serum potassium >5.5 mmol/l [10]. Current guideline-directed medical therapy endorses the combination of an ACEi or ARB or ARNI with an MRA to reduce morbidity and mortality in patients with chronic systolic heart failure [6]. The use of these agents in certain individuals may lead to hyperkalemia and prompt discontinuation of one or both drugs secondary to increased risk of life-threatening arrhythmia and/or death. This signals the need for a novel potassium binder (K-binder) with a more favorable side effect profile.

Patiromer

Patiromer is a non-absorbed polymer which primarily reduces serum potassium by exchanging potassium for calcium within the gastrointestinal tract [57]. PEARL-HF trial investigated the role of this novel agent in normokalemic patients with chronic heart failure (preserved and reduced ejection fraction) and chronic kidney disease (estimated glomerular filtration rate < 60 ml/min/1.73m2) or history of hyperkalemia leading to discontinuation of RAAS blockade therapy [13]. In this double blind, randomized, placebo-controlled trial, patients were treated with both spironolactone (escalating doses) and either patiromer or placebo. The patiromer group had a lower incidence of hyperkalemia (7 versus 25%, p = 0.015) and were more likely to achieve a higher daily dose of spironolactone at 50 mg/day (91 versus 74%, p = 0.019). Notably, these results were replicated in the subgroup of patients with renal disease without significant compromise to renal function. Over the course of 4 weeks, the patiromer group achieved significantly lower potassium levels, with a difference of 0.45 mEq/L between the two arms [13].

Adverse effects were more commonly seen in the patiromer group and included hypomagnesemia, flatulence, diarrhea, constipation, and vomiting. However, rates of termination between the two groups were similar [13]. Other things to consider include delayed onset of action and drug-drug interactions. To avoid this potential complication, it should be administered 6 h before or after other oral medications and serum magnesium levels should be monitored. Additional investigation is warranted to further evaluate impact on drug interactions as it may impact the pharmacokinetics of specific drugs. This trial and others led to the FDA approval of patiromer for the treatment of non-emergent hyperkalemia [15, 58, 59].

While the novel K-binder, patiromer, represents a useful therapy for the management of chronic hyperkalemia, there is also evidence that patiromer decreases serum aldosterone independent of plasma renin activity in patients with chronic kidney disease on RAAS-inhibiting therapy [60].

Sodium zirconium cyclosilicate (ZS-9)

Sodium zirconium cyclosilicate (ZS-9) is a highly selective inorganic cation exchanger, which specifically binds monovalent cations such as potassium as opposed to divalent cations, like patiromer, and is not systemically absorbed. It has also been proven safe as an efficient oral treatment for non-emergent hyperkalemia [61]. HARMONIZE was a multicenter, national, and international randomized, double-blind, placebo-controlled trial evaluating the impact of ZS-9 on potassium reduction in outpatients with known hyperkalemia (serum potassium ≥5.1 mEq/L). During the open-label phase, patients receiving ZS-9 included a diverse cohort: heart failure (36.4%), chronic kidney disease (65.5%), and diabetes mellitus (65.9%). In addition, 69.8% of individuals were receiving RAAS inhibitor medication. At baseline, the mean serum potassium was 5.6 mEq/L and the mean GFR was 46.3 ml/min/1.72 m2. Treatment with ZS-9 resulted in significantly lower mean serum potassium compared to placebo. Notably, the time to normokalemia was short—serum potassium was normal in 84% of patients at 24 h and 98% at 48 h. In the open-label phase, median time to normokalemia was 2.2 h [16].

Side effects of ZS-9 included edema, a dose-dependent effect was seen. Other adverse effects included anemia, nasopharyngitis, and mild hypokalemia. Aside from hypokalemia, no other significant electrolyte abnormalities were noted. There were no clinically significant arrhythmias [16]. In addition, no significant drug-drug interactions have been identified with ZS-9 [62]. This medication is currently undergoing evaluation by the FDA.

Overall, these new oral potassium binders: patiromer and ZS-9 appear to be safe, reasonably well tolerated, and efficacious. Their availability may allow clinicians to achieve higher doses of RAAS inhibiting medications in patients with heart failure and may provide beneficial pleiotropic effects which also warrant additional investigation.

Conclusion

The management of heart failure has undergone several paradigm shifts over the last century. Modern clinical practice has evolved from the vasodilator hypothesis to a deeper understanding of neurohormonal modulation to mechanical devices; it is through these experiences that our knowledge surrounding the complex pathophysiology of heart failure has continued to advance. Novel medications such as ARNI and If channel blockers are now encompassed in guideline-based management for patients with HFrEF. For those drugs which are clinically available such as K-binders and SGLT2 inhibitors, long-term safety and efficacy data in HFrEF populations remain critical. Other potential novel targets involve activation of cardiac myosin. In a phase 2 study, omecamtiv mecarbil was associated with improved cardiac function, reduction in ventricular diameter, and decrease in N-terminal pro B-type natriuretic peptide concentration [63]. Additional therapies for the treatment of acute heart failure, a domain which has lacked significant advances, are underway. Serelaxin is a recombinant form of the human peptide relaxin-2. This peptide regulates increases in maternal renal blood flow, arterial compliance, and cardiac output in pregnancy. The potential benefits of these physiologic changes in acute heart failure have shown inconclusive results in the acute setting; however, research is ongoing [64,65,66]. Investigation of sacubitril-valsartan in the acute setting is also underway (https://clinicaltrials.gov/ct2/show/NCT02554890). Future advancements in prevention and management will hopefully promote a decrease in morbidity and mortality through adoption of strategic interventions supporting the use of current and future guideline-directed therapies.